Oxo-pentamethylene-imidazolidines



United States Patent.

3,334,114 0X0-PENTAMETHYLENE-IMIDAZOLIDINES Rudolf G. Griot, FlorhamPark, N.J., assignor to Sandoz Inc., Hanover, NJ. No Drawing. Filed Mar.4, 1964, Ser. No. 349,487 28 Claims. (Cl. 260-309.7)

This invention concerns S-oxo-l,2-pentamethylene-imidazolidines,intermediates therefor, pharmaceutically acceptable acid addition saltsthereof and methods for preparing same. The Ibasic structure of thesecompounds is reflected by the formula M r 3,334,114 C Patented Aug. 1,1967 The primary u-arnino acid, H NRC0OH, is one wherein l R is R |CREach of R and R is, independently, either hydrogen (H); lower alkyl,e.g. methyl, isopropyl and butyl; hy-

Ra droxy (lower) alkyl, e.g. u-hydroxyethyl; lower alkyl thio 1 loweralkyl, e.g. methyl thioethyl; phenyl(lower)alkyl, e.g. benzyl;substituted benzyl wherein the substituents comprise hydroxy (OH),bromine (Br) and iodine (1) (I) and are directly bound to a ring carbonatom, e.g.

parahydroxybenzyl; indolyl(lower)alkyl, e.g. 3-indolyl-- methyl;irnidazole(lower)alkyl, e.g. 4(or 5)-imidazolemethyl; and phenyl.According to this invention, R independently, has any of the meetings ofR Alternatively, R and R are, together, either a saturated, e.g.p'entamethylene, or an ethylenically unsaturated, e.g. pentadienyl-1,3-,hydrocarbon chain. According to this definition, R and R together withthe carbon atom to which they are both attached form a carbocyclic ringof from 3 to 9 carbon atoms.

The following Table A reflects some of the contemplated primary a-aminoacids and the corresponding definitions of R and R TABLE A Name FormulaR1 R:

1. G1yc1ne. CHANHQ) OOOH H H 2. zit-Alanine CHaOH(NHi) c0011 OH: H 3.Serine HOOHrCH(NHz)COOH HOCH; H 4. Threonlne" CH3OH(OH)CH(NH2)OOOHcmoHwH H s. Vallne orrmonoHmrmcooH (cumcH H e. MethionineoHaswmnoHmm)OOOH CHIS(CHI)I H 1. Phenylalanine Q-omcnmno 00011 @011, H

Br Br 8. Dibromotyrosine HO--CH1CH(NH2)COOH BIO-@411, H

| I Br Br Q Q 9. Tryptophane NE I N\H\ H Hc=o CHnCH(NH )COOH Hc=o am 5 5f r r 3 10. His Hc "CHCH NH9)COOH :0 OH: H 11. kt-Ammo lsobutyric acidHzH 0 (CH3) =0 0 OH OH; CH, 12. a-Phenyl glycine Q-CH IH 0001: Q H

13. a-Amlno-cyclohexane carbonic acid- -CH1CHzCH,OH;CH

own

14. a-Methyl-a-phenyl glycine HzNC (CH3) 0 O OH Q CH;

The compounds of this invention are prepared in several steps startingwith an alpha-amino acid and any caprolactim ether, such as a loweralkyl ether, e.g. the methyl or ethyl ether, or corresponding thioetheraccording to the See Liebigs Ann., 623, 166 (1959); German Patent1,082,268 and US. Patent 3,002,000 for the preparation (VI) wherein eachof R and R has its previously ascribed meaning; R is lower alkyl, e.g.methyl, ethyl, propyl, isopropyl, butyl and amyl; and Z is a halogen,e.g. chlorine and bromine, atom.

Other substituents are introduced and corresponding acid addition saltsare prepared according to methods exemplified in the specific exampleswhich follow.

An alternative method of producing compounds (V) and (VI) starts withthe carbobenzoxy-a-amino acid chloride (VII) with proceeds accordingeither to reaction (F) or reaction (G).

of caprolactim methyl ether, reference is made to Benson, R. E., andCairns, T. L., J.A.C.S., 70, 2115 (1948).

In equations (A), (B) and (C):

each of R and R has the definition hereinbefore ascribed I thereto; R iseither lower alkyl, e.g. methyl, ethyl, isopropyl and 1butyl; phenyl; orphenyl(lower)a1kyl, e.g. benzyl; and Y is either oxygen or sulfur.

Methylation of (V) may be elfected according to procedure reported byEschweiler and Clarke, J .A.C.S., 55, 4571 (1933) [a special case of theLeuckhard Reac- 60 tion-compare Organic Reactions, V, page 305]:

(VI a) A more general alkylation procedure, however, is:

In reactions (F) and (G) R is either hydrogen (H) or lower alkyl,preferably lower alkyl with from one to four carbon atoms, e.g. methyl,ethyl, propyl and butyl. Whether (V) or (VI) is produced depends onlyupon whether R is hydrogen or lower alkyl. R and R have the samemeanings as heretofore defined.

Compounds (X) are novel intermediates which are exemplified by thecompound wherein each of R and R is hydrogen (H) and R is methyl (CH Toprepare a compound (X) with substituents in each of positions, R R and Rone starts with a compound, such as 2-Inethylamino-isobutyric acid (seeBeilstein H4, 41 6), and carbobenzoxylates same (see Greenstein, JesseP., and Winitz, Milton, Chemistry of the Amino Acids, vol. 2, page 891,John Wiley & Sons, Inc., 1961). The corresponding acid chloride is thenprepared from the carbobenzoxylated a-amino acid (Greenstein, Jesse P.,

- and Winitz, Milton, ibid, pages 965 to 968). The obtained acidchloride is then reacted with caprolactam. The reaction product istreated with an acetic acid solution of hydrogen bromide, as indicatedby reaction (G), to yield the compound of the formula mo CH;

The acid addition salts are those which are pharmacologically acceptableand include, inter alia, the hydrochlorides, fumarates, maleinates,tartrates, methane sulfonates, salicylates and hydrosulfates. The acidaddition salts of compounds (IV) are intermediates for the correspondingacid addition salts of compounds (V) and (VI). All acid addition saltsof compounds (V) and (VI), and their precursors, are within the scope ofthis invention. Those which are not therapeutically acceptable can beconverted to their corresponding free bases or to pharmaceuticallyacceptable acid addition salts by known EXAMPLE 1 Methanol adduct ofN-(azacycloheptan-Z-yl) aminoacetic acid NR2 H30-0-| Suspend 11.25 partsof glycine (0.15 mole) in 70 parts by volume of methanol and stirvigorously. To the resulting suspension add (in one portion) 25 parts(0.225 mole) of caprolactim-methylether, and stir the product at roomtemperature (about 20) over night (17 to 20 hours). Reaction (A) takesplace.

Add 70 parts by volume of diethyl ether to the resultant admixture, andfilter the crystalline reaction product produced. Dry said crystallinereaction product at 60/ 12 millimeters ('mm.) Hg for from two to fourhours to obtain crude (yet sufficiently pure) title compound containingone molecule of methanol; melting point (M.P.) 174 with decomposition.The yield thus obtained is between 90 and 100 percent by weight based onthe initial weight of glycine-employed.

EXAMPLE 2 5-oxo-L2-pentamethylene-imidazoline N N 1120/ --H2() 20 .CH3OHI HN -CH3OH N O=COH Place 27 parts (0.133 mole) of the methanol adduct(M.P. 174), prepared according to Example 1, in a round bottomed flaskconnected to a water separator. Add thereto a mixture of- 200 parts byvolume of toluene and 20 parts by volume (containing 0.100 part ofparatoluenesulfonic acid) of dimethylformanide. Heat the resultingadmixture to reflux.

Remove the first 50 parts by volume of refluxing solvent which containsthe adducted methanol of the starting material. Reflux the remainder forabout two hours (until no more water is split off and the boilingmaterial is fully dissolved). Remove the solvents by distillation from awater bath in vacuo (10 mm. Hg). Distill the remaining yellow-greencolored oil from an oil bath in vacuo'. The boiling point (B.P.) of thedistillate is 90/ 0.01 mm. Hg. The yield is about 70 percent by weightbased upon the weight of the starting methanol adduct. The oil productis viscous and solidifies at room temperature.

An analysis of said product, C H N O, revealsCalculated: C, 63.1%; H,8.0%; N, 18.4%. Found: C, 63.1%; H, 7.9%; N, 18.2%.

EXAMPLE 3 Hydrochloride of 5-0xo-1,Z-pentamethylene-imidazoline i O NDissolve the oil product of Example 2 in equal parts of isopropanol. Tothe resulting solution add suflicient 20 percent hydrogen chloride (inisopropanol) to neutralize said oil product. Precipitate the titlehydrochloride by cooling the neutralized material to 0. Saidhydrochloride precipitates as colorless leaves, M.P. 243. Filter theprecipitate from its mother liquor. Add dry diethylether to the motherliquor filtrate until the resulting solution .turns turbid. A furtheramount of crystals of the title hydrochloride is thus obtained. Thetotal yield is from to percent by weight based upon the starting weightof the oil product of Example 2.

An analysis of the hydrochloride, C H N O-HCl, revealsCalculated: C,50.9%; H, 6.9%; N, 14.8%; C1, 18.8%. Found: C, 51.1%; H, 7.3%; N, 14.5%;C1, 18.9%.

EXAMPLE 4 5-0x0-1,2-pentamethylme-imidazolidine Dissolve 410 parts(0.0264 mole) of 5-oxo-1,2-penta methylene-imidazoline (the titlecompound of Example 2 in free base form) in 20 parts by volume of 80percent (aqueous) acetic acid. Add 0.2 part of platinum dioxide to theresulting solution, and hydrogenate the produced mixture in ParrApparatus, starting at a pressure of about 50 pounds per square inch(p.s.i.g.).

When the hydrogenation is complete, filter olf the catalyst andevaporate the solvent in vacuo. The remainder is the acetic acidaddition salt of the title compound. Dissolve said salt in 20 parts byvolume of water. Add thereto 10 parts of potassium carbonate. Extractthe resulting solution with chloroform in a continuous extractionapparatus (Kutscher-Steudel type) until the aqueous phase is exhausted.Dry over potassium carbonate and remove the remaining solvent in vacuo.Distil.

The yield of the title compound /0.01 mm.) is about 80 percent based onthe weight of the initial free base. In similar manner all acid additionsalts of compounds (I) are converted into the corresponding free base.

The hydrochloride of the title compound is prepared according to thesame procedure starting with the hydrochloride of Example 3 (instead ofthe title compound of Example 2) and using ethyl alcohol as the solventin place of acetic acid.

The hydrochloride of the title compound is also prepared in the samemanner as described in Example 3, but starting with the title compoundof Example 4, rather than that of Example 2. Said hydrochloride,recrystallized from methanol/ether, melts at 164.

An analysis of said hydrochloride, C H N O-HCl revealsCalculated: C,50.4%; H, 7.9%; N, 14.7%; C1, 18.6%. Found: C, 50.3%; H, 8.0%; N, 14.8%;C1, 18.5%. Hydrochlorides of all compounds (I) are prepared in thismanner.

The maleinate of the title (base) is also readily prepared. Dissolveequivalent amounts of maleic acid and said base in absolute (ethyl)alcohol, and add diethyl ether to the resultant solution. The maleinateformed precipitates overnight. Recrystallize from methanol.

In similar manner any acid addition salt may be prepared from anycompound (I).

EXAMPLE 5 3-methyl-5-0x0-1 ,Z-pentamethylene-imidazolidine N N HCHO I O=N HO O OH O N 7 nitrogen in an oil bath of 120 for 3 hours. Add 10 partsby volume of 2 N hydrochloric acid, and evaporate the resulting solutionin vacuo to dryness.

Dissolve the residue (containing crude hydrochloride of the titlecompound and formaldehyde polymer) in 10 parts of water, and extract theproduct several times with ethyl acetate.

Add slowly (to avoid excessive foaming) 5 parts of potassium carbonate(K CO to the aqeous phase, and extract the free base (the titlecompound) from the resultant with chloroform in a continuous extractionapparatus. Dry the produced chloroform solution over potassiumcarbonate, and then evaporate the solvent. Distil the secondary amine invacuo, B.P. 80 to 84 /0.12 mm. Hg. A yield of 1.8 to 2.0 parts of saidsecondary amine is thus obtained.

To form the hydrochloride of the title (base) compound, neutralize thebase with a 20 percent (in isopropanol) solution of hydrogen chloridegas, add acetone to the product, and cool to 0. The hydrochlorideprecipitates in crystalline form. Filter the precipitate, and wash samewith acetone/ether (1:1), M.P. 173 to 175. The yield thus obtained isfrom 75 to 80 percent based on the weight of the starting base compound.

An analysis of said hydrochloride, C H CIN O, reveals-Calculated: C,52.8%; H, 8.4%; N, 13.7%; C1, 17.3%. Found: C, 52.3%;H, 8.5%;N, 13.8%;CI, 17.4%.

EXAMPLE 6 3-acezyl-5-0xo-1,Z-pentamezhylene-imidazolidine (7H3 C=O H I NAcetyl- N I chloride I I O N pyridine O N Add 4.24 parts ofacetylchloride to a frozen mixture of 7.13 parts of the title compoundof Example 4 in 70 parts by volume of benzene and 7.25 parts ofpyridine, and keep the resultant refrigerated (about 8) over night (17to 19 hours). Admix the thus-obtained material with 100 parts by volumeof ice-water and make alkaline with 2 N sodium carbonate (Na CO Extractthe product with chloroform.

Evaporate the solvent. The residue becomes crystalline. Recrystallizesaid crystalline residue from acetone/cyclohexane. The yield thusobtained is 4.9 parts, M.P. 108 to 109".

An analysis of the recrystallized title compound, C H N Oreveals-Calculated: C, 61.2%; H, 8.2%; N, 14.3%; 0, 16.3%. Found: C,61.3%; H, 8.4%; N, 14.1%; 0, 16.5%.

EXAMPLE 7 3 -ni troso-S -0xo-1 ,Z-pentamethylene-imidazolidine EN 02 o NO N Dissolve 6.0 parts (0.04 mole) of secondary amine (title compound ofExample 4) in 30 parts by volume of 1:1 HCl/H O. Stir the resultingsolution while adding thereto 1.5 equivalents of sodium nitrate (NaNO inthe form of a concentrated aqueous solution, and heating at a sulficientrate to maintain the ensuing reaction temperature at at most roomtemperature, i.e. about 20.

When the reaction is completed, allow the resulting admixture to standat room temperature for 24 hours. An oil separates. Extract the oil withchloroform. Dry the oil/chloroform extract and evaporate the solventtherefrom. Distil the residue at 100/ 0.037 mm. Hg. Recrystallize thesolid distillate from diethylether, M.P. 68 to 69.

8 An analysis of the recrystallized product, C H N O reveals Calculated:C, 52.4%; H, 7.2%; N, 22.9%; 0, 17.5%. Found: C, 52.9%; H, 7.3%; N,22.8%; 0, 17.4%.

EXAMPLE 8 3-amin0-5-0x0-1,Z-pentamethylene-imidazolidine hydrochlorideITTO N zine acetic O-- N acid IfHr IIIH,

Dissolve 2.0 parts of nitroso compound (title compound of Example 7) in30 parts by volume of acetic acid. Add gradually 5 parts of zinc metaldust to the resulting solution while stirring at 20. Continue thestirring for an additional hour. Filter. Add an excess of 30% (aq.)sodium hydroxide to the residue to render same alkaline. Extract thebase from the alkaline product with chloroform. Remove the solvent invacuo. Acidify the remaining crude amine (the free base corresponding tothe title compound) with an isopropanol solution of hydrogen chloride.Add charcoal to the resulting solution to decolorize same. Filter Offthe charcoal, and add diethyl ether to the filtrate. The titlehydrochloride is thus precipitated. Recrystallize the precipitatedhydrochloride from diethylether/ethanol, M.P. 192 with decomposition.

An analysis of the recrystallized product,

reveals-Calculated: N, 20.1%; C1, 17.3%. Found: N, 20.4%; C1, 17.0%.

EXAMPLE 9 3-propynyl-5-0x0-1,Z-pentamethylene-im-idazolidine Admix 23.0parts of secondary amine (title compound of Example 4), 25 parts ofpotassium iodide and 200 parts by volume of dirnethylformamide (DMF).Heat the resulting admixture of on a boiling water bath. Add dropwisethereto 20.8 parts of propargyl bromide, and thereafter maintain theresultant reaction mixture at 100 for two hours.

Evaporate the solvent in vacuo. To free the base (title compound), addaqueous potassium carbonate solution to the residue. Evaporate theobtained organic phase. Distil the remaining oil, B.P. 0.005 mm. Hg.

The hydrochloride, prepared from said oil in a manner analogous to thatdescribed in Example 3, melts at 162 to 163 after recrystallization fromisopropanol.

An analysis of the hydrochloride, C H N OCI, revealsCalculated: C,57.8%; H, 7.5%; N, 12.2%; 0, 7.0%; Ci, 15.5%. Found: C, 57.5%; H, 7.7%;N, 12.1%; 0, 7.0%; Ci, 15.9%.

EXAMPLE 10 3-propenyl-5-0xo-I ,Z-pentamethylen e-imidazolidine H C=CH2Admix 23.0 parts of secondary amine (title compound of Example 4), 25parts of potassium iodide and 200 parts by volume of DMF. Heat theresulting admixture to 100 on a boiling water bath. Add dropwise thereto21.2 parts of allyl bromide, and thereafter maintain the resultantreaction mixture at 100 for two hours.

Evaporate the solvent in vacuo. To free the base (title compound), addaqueous potassium carbonate solution to the residue. Evaporate theobtained organic phase. Distil the remaining oil, B.P. 103/0.1 mm. Hg.The refractive index, of said oil is 1.509.

A 72 percent yield, based on the Weight of starting amine, is thusobtained.

An elemental analysis of the product, C H N O, revealsCalculated: C,68.0%; H, 9.3%; N, 14.4%. Found: C, 67.3%; H, 9.4%; N, 14.5%.

To prepare the oxalate of the title compound, dissolve the latter inabsolute ethanol. Add to the resultant equivalent (equirnolecularamount) of oxalic acid dissolved in methanol/ethanol. To the product adddiethyl ether until crystals precipitate. Said crystals are the desiredoxalate, M.P. 112 to 113.

An elemental analysis of the oxalate, C H N O revealsCalculated: C,54.9%; H, 7.1%; N, 9.9%; O, 28.1%. Found: C, 55.1%; H, 7.3%; N, 9.7%; O,28.1%.

Other acid addition salts are prepared from the title compound and fromall compounds (I) in an analogous manner. The methanesulfonate, preparedin this manner, M.P. 116 to 117, has an elemental analysis, C H N OSCalculated: C, 49.6%; H, 7.6%; N, 9.6%; S, 11.0%. Found: C, 49.6%; H,7.9%; N, 9.3%; S, 11.2%.

EXAMPLE l1 3-pr0pyl-5-0x0-1,Z-pentamethylene-imidazolidine Reflux amixture of 6.18 parts of secondary amine (title compound of Example 4),parts of potassium iodide, 2.25 parts of 1,4-diazobicyclo[2,2,2] octaneand 100 parts by volume of 95% ethanol (aq.). Add 4.92 parts ofbromopropane slowly to the refluxing mixture. After refluxing theresultant reaction admixture for 18 hours, evaporate the solventtherefrom. Free the base, i.e. work up the residue, in the same manneras described in Examples 9 and 10. Add aqueous potassium carbonatesolution tosaid residue. Evaporate the obtained organic phase. Distilthe remaining oil in vacuo. A mixture of the secondary amine (titlecompound of Example 4) and the instant title compound is thus obtained.

Precipitate the-maleinate (4 parts) of said secondary amine (see Example4) and separate the precipitate by filtration. Evaporate the solventfrom the filtrate. Add

aqueous potassium, carbonate solution to the residue.-

Evaporate the obtained organic phase. Distil the remaining oil in vacuo.1.1 part of the title compound, B.P. 80 to 85 /0.01 mm. Hg, =1.495, isthus obtained.

The results of an elemental analysis for C H N O are-Calculated: C,67.3%; H, 10.3%; N, 14.3%. Found: C, 67.4%; H, 10.5%; N, 14.5%.

srcn ca cir ti) f Hydrogenate in ethanolic solution the title compoundof Example 10 using platinum dioxide as hydrogenation catalyst. Theinstant title compound is thus produced, as confirmed by infraredspectra.

EXAMPLE 12 Heat for fifteen hours on a boiling waterbath a mixture of 23parts of secondary amine (title compound of Example 4), 200 parts byvolume of DMF, 25 parts of potassium iodide and 27.3 parts of'y-chlorobutyrophenone. Evaporate the solvent in vacuo from theresultant. Admix aqueous potassium carbonate solution with the residueuntil the admixture is alkaline. Extract the title (base) compound fromthe alkaline admixture with chloroform. Distil the base, B.P. to /0.005mm. Hg, to obtain 5.6 parts of viscous oil.

Neutralize the viscous oil with an ethanolic solution of hydrogenchloride. To the product add acetone. The hydrochloride, M.P. 165.5 to167.5, is thus precipitated as crystals. An elemental analysis of saidhydrochloride, C H ClN O yields-Calculated: C, 64.2%; H, 7.5%; N, 8.3%;Cl, 10.5%; 0, 9.5%. Found: C, 64.1%; H, 7.6%; N, 8.5%; CI, 10.9%; 0,9.6%.

EXAMPLE 13 3- [4 (1 '-p-fluor0pheny l-1 -0x0) -butyl]-5-0x0-1,2-pentamethylene-imidazolidine hydroiodide (CHm-oO-QF EXAMPLE14 3-benzyl-5 -0xo-1 ,Z-pentamethylene-imidolidine "Heat to 100 on aboiling waterbath a mixture of 23.0 parts of secondary amine (titlecompound of Example 4), 25 parts of potassium iodide and 200 parts byvolume of DMF. To the resultant admixture add 29.9 parts of benzylbromide dropwise, and thereafter maintain same at 100 for two hours.

Evaporate the solvent in vacuo, and set the base (title compound) freewith aqueous potassium carbonate solution. Evaporate the organic phase,and distil the remaining oil, B.P. 135/0.008 mm. Hg, ==1.5547.

The hydrochloride (prepared as heretofore described) recrystallized fromisopropanol has a melting point at 170 to 171.

An elemental analysis of the hydrochloride,

yieldsCalculated: C, 64.2%; H, 7.5%; N, 10.0%; Cl, 12.6%. Found: C,64.3%; H, 7.8%; N, 9.3%; Ci, 12.8%.

EXAMPLE 15 4-methyl-5-0x0-1,2-pentamethylene-imidazolidine i N N rrtojH2 H3Cl N [Pt] o= EXAMPLE 16 3,4-dimethyl-5-ox0-1,2-pentamethylene-imidazoline Dissolve 33 parts (0.196 mole) of thetitle compound of Example 15 in 100 parts by volume of DMF. To theresulting solution add 30.8 parts (0.216 mole) of methyliodide. Anexothermic reaction is thus initiated.

After one half hour distil the reaction mixture in vacuo to remove thesolvent. Dissolve the residue in water, and set the base free withpotassium carbonate. Extract the amine (title compound) from theresultant with chloroform. Dry the produced solution over potassiumcarbonate, and thereafter remove the solvent therefrom. Distil theresidue. B.P. 83 to 85/0.3 mm. Hg, =1.498. A yield of the title compoundof 33.6 percent, based on the starting weight of the title compound ofExample 15, is thus obtained.

To prepare the corresponding hydrochloride, dissolve the base (instanttitle compound) in methanol. Neutralize the resultant with anisopropanolic solution of hydrogen chloride. Add ether and refrigerate(at about 8). The hydrochloride, M.P. 188 to 189.5, thus precipitateswith a yield of 94.5 percent (based on the starting weight of the titlecompound).

An elemental analysis of the hydrochloride,

162%. Found: C, 54.4%; H, 8.8%; N, 12.7%; CI, 15.8%. As is readily seen,for example, from Examples 10 12 to 16, substituents are readilyintroduced on the basic nitrogen atom (the 3-position) of the (secondaryamino) imidazolidine by reacting same with a halide according to thereaction:

wherein each of R and R has its heretofore defined meaning,

R is hydrocarbon [saturatedlower alkyl, e.g. propyl,

or lower cycloalkyl, e.g. cyclohexyl; ethylenically unsaturated loweraliphatic, e.g. allyl; acetylenically unsaturated lower aliphatic, e.g.propargyl; phenyl; monocarbocyclic ar(lower)alkyl, e.g. benzyl] orcarboxylic acid acyl [(lower)alkyl-keto(lower)alkyl, e.g.propylketo-ethyl; unsubstituted phenyl-keto-(lower) alkyl, e.g.phenyl-keto-propyl; substituted phenyl-keto-(lower) alkyl, e.g.p-fluorophenyl-keto-propyl]; and

X is a halogen, e.g. chlorine and bromine, atom.

As is readily appreciated, reaction (G) permits the introduction intothe indicated position of innumerable diverse substituents far beyondthose instantly exemplified.

All of the compounds of the instant invention possess central nervoussystem (CNS) activity and are useful accordingly. They are administeredeither orally or parenterally in daily doses of milligrams. Anindication of the spectra of activity and utility of a cross section ofcompounds according to this invention is reflected in the followingtable, wherein the compounds are all compounds of formula (VI). In eachof the compounds in the table R is a hydrogen (H) atom. R and R arespecifically set forth for each compound.

ACTIVITY AND UTILITY R1 31 Example H CHa 5 a d I i -H -COCH; 6 a b g 1-CH -CH 16 e h H -H 4 a c g i H CHz-CECH 9 a e g i H -CH2GE=CH 10 a c gl H O3H1 11 a b g l H OONH- a c g1 H --NO 7 a d f 1 H NH 8 a c g 1 --rr--(CH7)3-C 0Q 12 e 11 H NHCOCH a b g i -11 oH,)3-oo-r 12. e n

-H NHCH a b g 1 H writ-Q a b gt *a Monamine oxidase (MAO) inhibitingactivity.

b Produce CNS stimulation.

0 Produce either CNS depression or CNS depression followed bystimulation.

d Produce a stabilization of motor activity of mice in theactophotometer.

e Produce CNS depression and are not MAO inhibitors.

f Mood stabilizer.

g Psychic energizer.

h Sedative or sedative-hypnotic.

i Antihypertensive agent.

It is thought that the invention and its advantages will 20.3-[4'-(1'-parafluorophenyl 1' oxo)-butyl]--oxobe understood from theforegoing description. It is appar- 1,2-pentamethylene-imidazolidinehydroiodide. out that various changes may be made in the process, 21. 3benzyl-5-oxo-l,2-pentamethylene-imidazolidine. the intermediates and inthe final products without depart- 22.4-methyl-5-oxo-l,Z-pentamethylene-imidazolidine. ing from the spirit andscope of the invention or sacrific- 5 23. 3,4 dimethyl 5oxo-1,2-pentamethylene-imidazing its material advantages, the process,intermediates olidine. and final products hereinbefore described beingmerely 24. 3,4 dimethyl- 5 0X0-1,2-pentamethylene-imidazillustrative ofembodiments of the invention. olidine hydrochloride.

What is claimed is: 25. A compound of the formula 1. A compound of theformula R2 R3 OHPCH, I l CHzCH2 Rhikllpim 0H, 21i? O=C N \C 2 C zCHz-CH:

wherein each of R and R is, independently, a member wherein R is amember selected from the group conselected from the group consisting ofa hydrogen atom; lower alkyl, hydroxy(lower)alkyl; (lower) alkylthio(lower) alkyl; phenyl (lower) alkyl; benzyl sisting of a hydrogen atom,lower alkyl, hydroxy (lower) alkyl, (lower) alkylthio (lower) alkyl,phenyl (lower) alkyl, indolyl(lower) alkyl, imidazole(lower)ring-substitutedby a substituent selected from the y p y benlylSubstituted least one group consisting of hydroxy, a bromine atom andstituent selected from the group consisting of byan iodine atom;indolyl(lower)alkyl; imidazole (lowdroxy, bromo and iodo and, togetherwith R and the er)alkyl; and phenyl; and carbon atom to which both areattached, a carbo- R is a member selected from the group consisting ofcyclic ring of from 3 to 9 carbon atoms and selected a hydrogen atom,lower alkyl, lower alkenyl, lower from the group consisting of'asaturated ring and an alkynyl, (lower)alkylcarbonyl, amidobenzene,niethylenically unsaturated ring; and troso, primary amino, (lower)alkyl(secondary) R is a member selected from the group consisting of 21amino, phenyl(lower)a1kyl, (lower)alkylamido, hydrogen atom, loweralkyl, hydroxy(lower)alkyl, phenyl-keto-(lower)alkylene andpara-fluoro-keto- (lower)alkylthio (lower)alkyl, phenyl(lower)alky1,(lower)alkylene. 3O indolyl(lower)alkyl, imidazole(lower)alkyl, phenyl,2. A compound of the formula benzyl substituted by at least onesubstituent selected R2 R3 OHPCHZ from the group consisting of hydroxy,bromo and iodo and, together with R and the carbon atom to CH which bothare attached, a carbocyclic ring of from O=C-N z 3 to 9 carbon atoms andselected from the group con- CH sisting of a saturated ring and anethylenically un- 2 2 saturated ring; and wh i R1 a d R taken t g t Withthe imidazoli- R is a hydrocarbon radical selected from the group dine gcarbon atom tO which y are consisting of lower alkyl, lower alkenyl,lower alkynform an at most ethylenically unsaturated hydro- 40 yl, lowercycloalkyl, phenyl and monocarbocyclic carbon ring of from 3 to 9 carbonatoms; and ar(lower)alky1. R is a member selected from the groupconsisting of 26. A compound of the formula a hydrogen atom, loweralkyl, lower alkenyl, lower alkynyl, (lower)alkylcarbonyl, amidobenzene,nitro- R R CH2CH1 so, primary amino, (lower)alkyl(secondary)amino, 1phenyl(lower) alkyl, (lower)alkylamido, phenyl-keto- H, (lower)alkyleneand parafluorophenyl-keto-(lower) O=O N alkylene. CHr-OH: 3.S-oxo-1,2-pentamethylene-imidazolidine. 4, 5 0X0 1,2 pentamethylene iida lidi h d wherein R is a member selected from the group conchloride.sisting of a hydrogen atom, lower alkyl, hydroxy 5.S-oxo-l,Z-pentamethylene-imidazolidine maleinate. Y y y phenyl 6.3-methyl-5-oXo-1,2-pentamethylene-imidazolidine. y y y imidazoleflowef)7. 3 methyl 5 oxo l,2-pentamethylene-imidazolialkyl, phenyl, benzylsubstituted by at least one subdine hydrochloride. stituent selectedfrom the group consisting of hy- 8.3-acetyl-5-oxo-1,2-pentamethylene-imidazolidine. droxy, bromo and iodoand, together with R and 9.3-nitroso-5-oxo-1,2-pentamethylene-imidazolidine. the carbon atom towhich both are attached, a carbo- 10.3-amino-5-oxo-1,Z-pentamethylene-imidazolidine. cyclic ring of from 3 to9 carbon atoms and selected 11. 3 amino 5 oxo 1,2 pentamethylene-imidazofrom the group consisting of a saturated ring and an lidihydrochloride, ethylenically unsaturated ring; and

12. 3 propynyl 5-oxo-1,2-pentamethylene-imidazoli- R is a memberselected from the group consisting of a di hydrogen atom, lower alkyl,hydroxy(lower) alkyl, 13. 3 propynyl 5 0x0 1,2 pentamethylene-imid-(lower)alkylthio(lower)alkyl phenyl(lower) alkyl, azolidinehydrochloride. indolyl(lower)alkyl, imidazole(1ower)alkyl, phen- 14. 3propynyl 5-oxo-1,Z- entamethyIene-imidazoliyl, benzyl substituted by atleast one substituent dine. selected from the group consisting ofhydroxy, bromo 15. 3 propynyl 5 oxo 1,2 pentamethylene-imidand iodo and,together with R and the carbon atom azolidine oxalate. to which both areattached, a carbocyclic ring of 16. 3 propynyl 5 0X0 1,2pentamethylene-imidfrom 3 to 9 carbon atoms and selected from the groupazolidine methanesulfonate. consisting of a saturated ring and anethylenically 17. 3-propyl-5-oxo-1,Z-pentamethylene-imidazolidine.unsaturated ring; and 18. 3-[1'-(4-phenyl 4' oxo)-butyl]-5-oxo-1,2-penta- R is carboxylic acid acyl selected from the groupconmethylene-imidazolidine. sisting of (lower)alkyl carbonyl,(lower)alkyl-keto- 19. 3-[4-(1'-phenyl 1' oXo)-butyl]-5-oxo-l,2-penta-(lower)alkylene, phenyl-keto-(lower) alkylene andmethylene-imidazolidine hydrochloride. para-fluorophenyl-keto- (lower)alkylene.

27. A compound of the formula alkylene.

wherein R is a member selected from the group-consisting of a hydrogenatom, lower alkyl, hydroxy (lower)alkyl, (lower)alkylthio(lower)alkyl,phenyl (lower)alkyl, indolyl(lower)alkyl, imidazole(lower) CH O=C-I I 25 alkyl, phenyl, benzyl substituted by at least one sub- CHPOH2 stituentselected from the group consisting of hydroxy bromo and iodo andtogether with R and the 1 7 igg g g g gggz zgg g$ i g fifi g fgg carbonatom to which both are attached, a carbocyclic (lower)alky1,(lower)alkylthio(lower)alkyl, phenyl i of from 9 czgbon W selectedlower)alkyl, indolyl(lower)alkyl, imidazole(lower) 10 25:32: 3 5 2 2225g g jg rmg an ethy g gi :5:g gg gg j gig gfig 223$: s R is a memberselected from the group consisting of a droxy bromo and iodo andtogether with R and the hydrogen lower alkyl, Y(1 Wer)alkyl, carboh atomto which both are attached a carbo- .(lower)alkylthlouoweirlalkylphenymowenalkyl cyclic ring of from 3 .to 9 carbon atoms and selected 15mdolyluowef) alkyl lmldazoleuowenlalkyl phenyl from the g p consistingof a Saturated ring and an benzyl substituted by at least onesubstltuent selected gthylenicany unsaturated ring and from the groupcons sting1 of hydroxy, bromo and R is a member selected from the groupconsisting of a 3. fiogether l R the f p atfom to hydrogen atom loweralkyl hydroxy(lower)alkyl W 1C 0t are attac a Car ocyc 16 ring 0 from 203 to 9 carbon atoms and selected from the group (lower) a1kylth1o(lower)alkyl, phenyl(lower)alkyl, d d h I ll indolyl(lower)alkyl,imidazole(lower)alkyl, phenyl, l q nng an an et yemca benzyl substitutedby at least one substituent selected mate 2 i t d f th f from the groupconsisting of hydroxy, bromo and ls a mem er 56 ac e mm 6 groupconslstmg 0 a iodo and together with R and the carbon atom to hydrogenatom lower alkyl alkenyl which both are attached a carbocyclic ring offrom alkynyl (lower?alkyl'carbonyl amldobenzene m 3 to 9 carbon atomsand selected from the group conpnmary ammo (lowenalkyl (se.cndary)ammsisting of a saturated ring and an ethylenically unphenyluoweryalkyl(lower) alkylamldo phenyl'keto Saturated g and (lower)alkylene andpara-fluorophenyl-keto-(lower) R is a member selected from the groupconsisting of a alkylene' hydrogen atom, lower alkyl, lower alkenyl,lower References Cited alkynyl, (lower)alkyl-carbonyl, amidobenzene,nitro- UNITED STATES PATENTS so, primary amino, (lower) alkyl(secondary)amino phenyl(lower)alkyl, (lower)alkylamido, phenyl-keto3,002,000 9/1961 Tletze et a1 26O 309'6 (lower)alkylene andpara-fluorophenyl-keto-(lower) FOREIGN PATENTS 28. An acid addition saltof a compound of the formula 1082268 10/1960 Germany Iii 1'1 /OHCH1WALTER A. MODANCE, Primary Examiner. N. s. MILESTONE, Examiner.

N. TROUSOF, Assistant Examiner. GHQ-CH2

1. A COMPOUND OF THE FORMULA
 26. A COMPOUND OF THE FORMULA
 27. ACOMPOUND OF THE FORMULA